Rydapt

RYDAPT is a kinase inhibitor indicated for the treatment of adult patients with:

• Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. (
  1.1 Acute Myeloid Leukemia

  RYDAPT is indicated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA approved test

  [see Dosage and Administration (2.1), Clinical Studies (14.1)].

  Limitations of Use

  RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.
  )
  
  
  Limitations of Use:
  RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.
• Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). (
  1.2 Systemic Mastocytosis

  RYDAPT is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).
  )

• AML
  : 50 mg orally twice daily with food. (
  2.1 Patient Selection

  Select patients for the treatment of AML with RYDAPT based on the presence of FLT3 mutation positivity

  [see Clinical Studies (14)]

  . Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics.
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  2.2 Recommended Dosage in Acute Myeloid Leukemia

  The recommended dose of RYDAPT for patients with AML is 50 mg orally twice daily with food on Days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on Days 8 to 21 of each cycle of consolidation with high-dose cytarabine. For a description of the experience with single-agent treatment with RYDAPT beyond induction and consolidation

  [see Clinical Studies (14.1)]

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  2.4 Recommended Administration

  • Administer prophylactic anti-emetics before treatment with RYDAPT to reduce the risk of nausea and vomiting.
  • Administer RYDAPT orally with food, twice daily at approximately 12-hour intervals
    [see Clinical Pharmacology (12.3)].
    Do not open or crush RYDAPT capsules.
  • If a dose of RYDAPT is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
  • Consider interval assessments of QT by electrocardiogram (ECG) if RYDAPT is taken concurrently with medications that can prolong the QT interval.
  )
• ASM, SM-AHN, and MCL
  : 100 mg orally twice daily with food. (
  2.3 Recommended Dosage in ASM, SM-AHN, and MCL

  The recommended dose of RYDAPT for patients with ASM, SM-AHN, and MCL is 100 mg orally twice daily with food. Continue treatment until disease progression or unacceptable toxicity occurs. Table 1 provides recommendations for dose modifications of RYDAPT in patients with ASM, SM-AHN, and MCL. Monitor patients for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment.

  Table 1: RYDAPT Dose Modifications for Patients with Systemic Mastocytosis

  Criteria	RYDAPT Dosing
  ANC less than 1 x 109/L attributed to RYDAPT in patients without MCL, or ANC less than 0.5 x 109/L attributed to RYDAPT in patients with baseline ANC value of 0.5-1.5 x 109/L	Interrupt RYDAPT until ANC greater than or equal to 1 x 109/L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue RYDAPT if low ANC persists for greater than 21 days and is suspected to be related to RYDAPT.
  Platelet count less than 50 x 109/L attributed to RYDAPT in patients without MCL, or platelet count less than 25 x 109/L attributed to RYDAPT in patients with baseline platelet count of 25-75 x 109/L	Interrupt RYDAPT until platelet count greater than or equal to 50 x 109/L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low platelet count persists for greater than 21 days and is suspected to be related to RYDAPT.
  Hemoglobin less than 8 g/dL attributed to RYDAPT in patients without MCL, or life-threatening anemia attributed to RYDAPT in patients with baseline hemoglobin value of 8 to 10 g/dL	Interrupt RYDAPT until hemoglobin greater than or equal to 8 g/dL, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low hemoglobin persists for greater than 21 days and is suspected to be related to RYDAPT.
  Grade 3/4 nausea and/or vomiting despite optimal anti-emetic therapy	Interrupt RYDAPT for 3 days (6 doses), then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily.
  Other Grade 3/4 non-hematological toxicities	Interrupt RYDAPT until event has resolved to less than or equal to Grade 2, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily.
  Abbreviations: ANC, absolute neutrophil count; MCL, mast cell leukemia. National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) severity: Grade 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.
  ,
  2.4 Recommended Administration

  • Administer prophylactic anti-emetics before treatment with RYDAPT to reduce the risk of nausea and vomiting.
  • Administer RYDAPT orally with food, twice daily at approximately 12-hour intervals
    [see Clinical Pharmacology (12.3)].
    Do not open or crush RYDAPT capsules.
  • If a dose of RYDAPT is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
  • Consider interval assessments of QT by electrocardiogram (ECG) if RYDAPT is taken concurrently with medications that can prolong the QT interval.
  )

25 mg capsules: pale orange oblong soft capsule with red ink imprint ‘PKC NVR’.

• Embryo-Fetal Toxicity
  : RYDAPT may cause fetal harm when administered to a pregnant woman. Advise of the potential risk to a fetus. (
  5.1 Embryo-Fetal Toxicity

  Based on its mechanism of action and findings from animal reproduction studies, RYDAPT may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT therapy. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose

  [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)]

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  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RYDAPT during pregnancy. Females who may have been exposed to RYDAPT during pregnancy directly or through a male partner receiving RYDAPT therapy should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com/.

  Risk Summary

  Based on mechanism of action and findings in animal reproduction studies, RYDAPT may cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology (12.1)]

  . There are no available data on RYDAPT use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose

  (see Data)

  . Advise pregnant women of the potential risk to a fetus.

  The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Data

  Animal Data

  When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day [approximately 0.1 times the human exposure at the recommended dose based on area under the curve (AUC)], there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos.

  During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryo-fetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC).

  In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.
  )
• Pulmonary Toxicity
  : Monitor for symptoms of interstitial lung disease or pneumonitis. Discontinue RYDAPT in patients with signs or symptoms of pulmonary toxicity. Fatal cases have occurred. (
  5.2 Pulmonary Toxicity

  Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy.

  Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.
  )